Pharmaceutical formulations comprised of compacted amoxicillin granulates

ABSTRACT

The present invention discloses tablet formulations, produced by dry roller compaction comprising compacted granulates of a mixture of a medicament and an intra-granular disintegrant. The granulates are compacted together into a tablet with an extra-granular disintegrant, an optional extragranular lubricant and excipients.

This application is a divisional of U.S. Ser. No. 09/217,304, filed Dec.21, 1998, now U.S. Pat. No. 6,110,497, which is a divisional applicationof U.S. Ser. No. 08/729,222, filed Oct. 9, 1996, now U.S. Pat. No.5,851,550, which is a continuation of U.S. Ser. No. 08/146,069, filedJul. 14, 1994, abandoned, which is the §371 national stage entry ofPCT/EP92/01024, filed May 2, 1992.

The present invention relates to pharmaceutical formulations for oraladministration in the treatment of bacterial infections, and toprocesses for the manufacture of such formulations.

It is known to provide formulations for oral administration in the formof water-dispersible granules or tablets which may be swallowed ordispersed in water prior to swallowing.

In one known method of tablet manufacture, an intermediate granulate isprepared comprising an intragranular disintegrant and an active materialsuch as an antibiotic. This granulate is then mixed with anintergranular disintegrant (and optional other additives including alubricant) and compressed into tablets. Such a process, tablets andgranulate are for example described in EP 0281200A, CA 1199871 and JP3240023A.

It is desirable that such solid formulations should rapidly disperse onimmersion in water, for example by rapid disintegration of tablets.

Novel formulations have now been discovered which assist in achievingsome of the above-mentioned desirable features.

The invention therefore provides a tablet formulation having a structurecomprising compacted granulates; the granulates comprising at least onecompacted medicament optionally together with an intra-granulardisintegrant; the granulates being compacted together into a tablet formtogether with an extra-granular disintegrant and optionally alsotogether with an extra-granular lubricant, provided that if a lubricantis present the amount of lubricant is less than 0.5% by weight of thetotal tablet.

In the tablets of this invention the granulates may be in a crushedstate resulting from the compaction of the tablet, and consequently maynot have discrete boundaries, or may be sub-divided or broken up intosmaller granulates. The invention is intended to include tablets havingsuch a structure containing crushed granulates. Preferably the size ofthe granulates is in the range 100 μm to 2 mm, suitably around 1 mm±0.25mm, maximum dimension.

The medicament is preferably one which is capable of oral absorption, inparticular β-lactam antibiotics optionally in combination with aβ-lactamase inhibitor. A preferred antibiotic is amoxycillin, forexample present as a hydrate such as the trihydrate. Amoxycillin may beused alone, or may optionally be used in combination with other β-lactamantibiotics and/or β-lactamase inhibitors such as clavulanic acid orsalts (especially the potassium salt) thereof, for example in a weightratio equivalent to amoxycillin: clavulanic acid in the range 12:1 to1:1 such as around 4:1 or 2:1. Preferably the proportion of theantibiotic in the tablet is 60-98% by weight of the total tablet, in thecase of amoxycillin trihydrate calculated as the weight of thetrihydrate. Preferably the particles of antibiotic in the granulates arein the size range 1 μm to 300 μm, especially 10 μm to 200 μm. A typicalsuitable size distribution of the antibiotic particles is: >200μ 5% orless, 200-100μ 5-15%, 100-50μ 7.5-15%, <50μ 70% or more.

Suitable intra-granular disintegrants are starches, such as maize starchand rice starch, cross-linked N-vinyl-2-pyrrolidone (“CLPVP”), sodiumstarch glycollate, croscarmellose sodium and formaldehyde—casein, orcombinations thereof. A preferred intra-granular disintegrant is CLPVP,for example as marketed under the trade names Polyplasdone XL andPolyplasdone XL-10.

The granulate may consist entirely of antibiotic(s), optionally in thecase of a β-lactam antibiotic combined with a β-lactamase inhibitor, andan intra-granular disintegrant. Alternatively, particularly when thegranulate contains clavulanic acid or a salt thereof, the granulate mayalso contain a diluent such as silica gel (eg Syloid-Trade Mark).Suitable intra-granular disintegrants for use with antibiotics are CLPVPand sodium starch glycollate. Typically the proportion of intra-granulardisintegrant in the granulate may be 0.1-10 wt % of the granulate,suitably 1.0-8.0 wt %, such as 1.25-3.5 wt %. Typically the proportionof an antibiotic or antibiotic+β-lactamase inhibitor combination in thegranulate may be 99.9-90 wt %, suitably 99-92 wt %, e.g. 99-95 wt %,such as 98.75-96.5 wt % of the weight of the granulate. When thegranulate contains a diluent, this may comprise up to 30 wt % of thegranulate, but is conveniently present in a 1:1 weight ratio with theamount of clavulanic acid or its salt in the granulate. When thegranulate contains a diluent the granulate will contain acorrespondingly lower proportion of antibiotic or antibiotic+β-lactamaseinhibitor combination, for example 70-99.9 wt % of the granulate.

The intimate contact between the antibiotic and the intra-granulardisintegrant in the granulate appears to assist in improveddisintegration and dispersion of the granulate in contact with water torelease antibiotic particles in the size range referred to above, and toprovide finely dispersed suspensions. Problems are associated withpreparation of granulates which include clavulanic acid or its salts,due to their hygroscopicity, and the granulate of the inventionfacilitates manufacture.

In the tablet formulation the granulate may suitably comprise 70% ormore, e.g. 80% or more, 90% or more or 95% or more of the total tabletweight so that a high proportion of medicament is present.

The extra-granular disintegrant may be a conventional disintegrant forexample starches such as maize-starch and rice starch, CLPVP, sodiumstarch glycollate, croscarmellose sodium, microcrystalline or microfinecellulose, low-substituted hydroxypropylcellulose (i.e. cellulosepartially substituted with 2-hydroxypropyl groups, e.g. less than 25%substituted, preferably 7-16% substituted), cross-linked sodiumcarboxymethylcellulose, swellable ion exchange resins,formaldehyde-casein, or alginates. Preferred extra-granulardisintegrants are CLPVP, sodium starch glycollate, microfine celluloseand croscarmellose sodium, and combinations thereof. An example of anextra-granular disintegrant combination is a combination ofmicrocrystalline or microfine cellulose with sodium starch glycollate,croscarmellose sodium, or CLPVP, containing 80-90% by weight cellulose.

The proportion of extra-granular disintegrant to total tablet weight mayvary between broad limits, for example 0.1-25 weight %. For example ifCLPVP or sodium starch glycollate is used as extra-granular disintegrantit may suitably be used as such in a proportion 0.1-5.0 weight %,suitably 0.1-3.0 weight %, preferably 0.1-1.5 weight % of the totaltablet weight. If cellulose or a combination containing cellulose isused, e.g. as described above containing around 80-90% by weight ofcellulose, the extra-granular disintegrant may comprise 1-25 weight %,typically around 1-20 weight % of the total tablet.

Suitable lubricants are those conventional to the art, such aslong-chain fatty acids, such as stearic acid, or salts thereof, inparticular Group II metal salts, such as of magnesium or calcium.

A preferred lubricant is magnesium stearate. It is preferred to use alubricant proportion as low is possible e.g. 0.35% by weight orpreferably lower, e.g. 0.275% or less, e.g. 0.25% or less, preferablyusing no lubricant at all.

The granulate may also contain an intra-granular lubricant, which may beselected from the same materials as the extra-granular lubricant, suchas magnesium stearate. However an advantage of the present tabletformulation is that the granulate and tablet need not contain anylubricant. This can lead to improved wettability and hence improveddisintegration of the tablet. Further a reduced lubricant proportion canlead to a lower tablet weight for a given dose of antibiotic and in thecase of dispersible formulations can avoid the “smeared” appearanceassociated with higher lubricant proportions.

The tablet may also include conventional excipients, typically presentup to about 10% of the total tablet weight. These may include flavouringagents, for example flavourings such as menthol, peppermint, vanilla orfruit flavourings, flavouring agents typically being present up toaround 0.5-5% by weight of the whole tablet, and sweeteners, e.g.aspartame, present of up to around 15 mg per unit dose. Excipients mayalso include colouring agents, preservatives, suspending aids andfillers such as silicon dioxide, microcrystalline cellulose, dicalciumphosphate, lactose, sorbitol, calcium carbonate or magnesium carbonate.Such excipients are preferably mixed with the extra-granulardisintegrant and lubricant (if present). The materials present in thetablets should have low free moisture content and preferably bepre-dried. In some cases, particularly when the medicament is anantibiotic, and includes clavulanic acid or its salts, it may benecessary to include a dessiccant diluent such as silica gel as anexcipient, in a proportion of about 1-5% of the weight of theantibiotic, mixed with the antibiotic and intra-granular disintegrant inthe granulates. The particle size of the excipients does not appear tobe critical but it is desirable to exclude agglomerates.

The tablet may also contain an effervescent couple of known type, e.g. asolid acid and an alkali metal carbonate or bicarbonate which generatescarbon dioxide on contact with water to assist in disintegration of thetablet.

The tablets may be film coated in a conventional manner, e.g. forcosmetic, palatability or production purposes. Suitable coatings includehydroxypropylcellulose, acrylate and/or methacrylate co-polymers, resinsetc. Alternatively the coating may be an enteric coating, e.g. which isinsoluble in acidic gastric juice but soluble in alkaline digestivejuice. Such a coating enables the antibiotic to pass through the stomachinto the duodenum, from where it is absorbed. Suitable enteric coatingsinclude cellulose acetate phthalate.

Preferred combinations of components for the tablets of this aspect ofthe invention therefore comprise:

Component wt % Example Granulate: Medicament 70-99 Amoxycillin ±Pot.clavulanate Disintegrant 0.1-4   CLPVP, Microcryst. cellulose,sodium starch glycollate Diluent  0-30 Silica gel Tablet: Granulate 70+above Disintegrant 0.1-25  CLPVP, Microcryst. cellulose, sodium starchglycollate. Lubricant   0-0.35 Magnesium stearate Excipients to 100Aspartame, flavour, colour, silicon dioxide

The invention also provides a process for the manufacture of a tablet inwhich granulates comprising a compacted mixture of at least onemedicament such as a β-lactam antibiotic either alone or in combinationwith a β-lactamase inhibitor, together with an intra-granulardisintegrant are mixed with an extra-granular disintegrant andoptionally with an extra-granular lubricant and optionally with anyexcipients, provided that if a lubricant is present it amounts to lessthan 0.5% by weight of the mixture, and the mixture is compressed intotablets.

Suitable and preferred antibiotics, intra- and extra-granulardisintegrants, lubricants, excipients, granulate and particle sizes, andrelative proportions thereof are as discussed above.

The necessary granulate for the process of this aspect of the inventionmay be made in a further process by mixing the medicament in a powderedform with the intra-granular disintegrant in a dry state, and compactingthe mixture under pressure. Insofar as this further process uses asintra-granular disintegrant CLPVP, sodium starch glycollate,casein-formaldehyde, croscarmellose sodium or combinations thereof, itis believed to be novel, and is a further aspect of this invention.

In this further process, it is desirable to mill and sieve theantibiotic to achieve the desired particle size range. It is alsodesirable to mill and sieve intra-granular disintegrant to a suitableparticle size, for example in the case of CLPVP about 30μ, but particlesize does not appear to be critical.

The compaction of the mixture into granulates may be by conventional drycompaction means, for example pressing, rolling, slugging extrusion etc,and a suitable pressure for the compaction process is 30-200 KN, e.g.35-65 KN preferably 40-50 KN. The above-described granulate formulationsare particularly suited to formation by roller compaction. It may benecessary to mill and sieve the compacted mixture after compaction so asto achieve a suitable size fraction of the granulate. Compression intotablets may be carried out in a conventional manner, e.g. on aconventional tabletting machine. As an optional further step the tabletsmay be coated as described above.

When the granulates described above contain as a medicament a β-lactamantibiotic such as amoxycillin together in combination with aβ-lactamase inhibitor such as clavulanic acid or its salts (especiallypotassium clavulanate) these granulates are believed to be novel and area further aspect of this invention. Suitable and preferred features ofthese granules are as discussed above.

The granulates described above may be suitable for use in thepreparation of other pharmaceutical formulations in addition to tablets,for example they may be supplied as a free-flowing granulatedformulation in sachets containing a suitable unit dose. This may alsofor example be dissolved in water together with excipients such assweetening agents, thickeners, preservatives and buffers such as sodiumbenzoate, sodium acetate and sodium citrate to form a syrupfonniulabinn, for example for administration to small children.

The ability of the granulates to form a loose compact, and their rapiddispersion in contact with water makes them particularly suitable foruse in encapsulated formulations. Therefore in a further aspect of thisinvention there is provided an encapsulated formulation comprising suchgranulates. The encapsulated formulation may optionally include anextra-granular lubricant, which if present is suitably in an amount ofless than 0.5% by weight of the granulates, being contained within apharmaceutical capsule.

The medicament is preferably one which is capable of oral absorption, inparticular a β-lactam antibiotic optionally in combination with aβ-lactamase inhibitor. Suitable and preferred antibiotics, β-lactamaseinhibitors, intra-granular disintegrant, extra-granular lubricant,granulate and particle sizes, and relative proportions thereof for acapsule formulation are as discussed above, except that a preferredproportion of lubricant is 0.1-0.5%, particularly 0.32-0.35% by weightof the granulate.

The pharmaceutical capsule may be an entirely conventional capsule,capable of dissolving in the stomach to release its contents, forexample made of gelatine.

The formulations described above preferably contain unit doses ofantibiotic, for example 375, 500, 750 or 1000 mg of amoxycillin pertablet or capsule. The tablets may be dispersed in water prior toingestion, or may alternatively be chewed or swallowed whole.

The invention further provides a pharmaceutical formulation as describedabove, for use as an active therapeutic substance.

The invention further provides a pharmaceutical formulation as describedabove, in which the medicament is a β-lactam antibiotic optionally incombination with a β-lactamase inhibitor, for use in the treatment ofbacterial infections.

The invention futher provides a method of use of a pharmaceuticalformulation as described above in which the medicament is a β-lactamantibiotic optionally in combination with a β-lactamase inhibitor in themanufacture of a medicament for use in the treatment of bacterialinfections.

The invention further provides a method of treament of bacterialinfections in mammals which comprises the administration to the mammalof an effective amount of a pharmaceutical formulation as describedabove, in which the medicament is a β-lactam antibiotic, optionally incombination with a β-lactamase inhibitor.

The invention will now be described by way of example only.

EXAMPLE 1

Granulate

Amoxycillin trihydrate was milled and sieved using an 0.04 or 0.027 inch(1.0-0.7 mm) aperture sieve, and was mixed for 15 minutes in a blenderwith dried cross-linked polyvinylpyrrolidone having a molecular weightof approximately 1 million and a density of 1.22 mg/cm 3 (polyplasdoneXL-Trade Mark), the mixture containing 3.4% of CLPVP by weight.

The mixture was consolidated using a roller compacter at a controlledpressure of 50 KN. The compacted flakes were granulated in a mill, orgranulated through a sieve fitted with a lmm mesh to obtain a suitablesize fraction.

EXAMPLE 2

Tablet

Tablets were prepared having the composition below;

Component Weight mg. Weight % Amoxycillin trihydrate 750¹ 78.95 asgranulate of CLPVP 26.0 2.73 example 1 Sodium Starch 21.6 2.27Glycollate (Primogel) Magnesium Stearate 2.0 0.21 Aspartame 20.0 2.10extra granulate Microcrystalline 130.4 13.74 Cellulose (Avicel PH102)¹Expressed or free acid equivalent: To prepare these tablets, the driedsodium starch glycollate, magnesium stearate and microcrystallinecellulose were sieved, then blended with the granulate of example 1. Theaspartame was then added, and this mixture was then blended untilhomogenous (5 minutes). The mixture was then compressed into tablets ona conventional tabletting machine.

EXAMPLE 3

Granulate

A granulate was prepared using a procedure identical to example 1,comprising 97 weight % of amoxycillin trihydrate and 3 weight %polyplasdone XL, and using a controlled pressure of 40-50 KN.

EXAMPLE 4

Tablet

Tablets were prepared having the composition below:

Component wt. mg wt. mg wt. mg wt. mg wt. % Amoxycillin 375 500 750 100083.00¹ CLPVP 17.5 23.33 35 46.65 3.78² Peppermint 3 4 6 7.99 0.65 dryflavour Aspartame 7.5 10 15 19.99 1.62 Magnesium 1 1.34 2 2.67 0.21stearate ¹As 95 wt. % of amoxycillin trihydrate. ²3% as intra-granular,and 0.78% as extra-granular disintegrant.

To prepare these tablets, the dried flavour, aspartame, magnesiumstearate and a weight of CLPVP (polyplasdone XL) corresponding to 0.78wt. % of the total weight of the mixture was mixed for 5 minutes withthe granulate of example 3 to give the wt % indicated above. The mixturewas then compressed into tablets on a conventional tabletting machine.

Typical tablets of this example containing 750 mg of amoxycillin as thetrihydrate had the following characteristics:

weight: 925 mg ± 5% hardness: >16 KP time of dispersal: <1 minute inwater friability: <1% presentation: Oval, 17 × 10 × 7 mm tablets

EXAMPLE 5

Granulate

A granulate was prepared using a procedure identical to that of example1, comprising 97.12 weight % amoxycillin trihydrate together with 2.88weight % sodium starch glycollate (as “Primogel”) as intra-granulardisintegrant.

EXAMPLE 6

Tablet

Tablets were prepared having the composition below:

Component % Weight mg. Weight % Amoxycillin 750 mg¹ 78.95 as granulateSodium starch 21.6 mg 2.27 of example 5 glycollate Magnesium stearate2.0 mg 0.21 Dried microcrystalline to 950 mg 18.57 extra granulatecellulose (Avicel PH102) ¹As free acid equivalent

To prepare these tablets, the granulate of example 5 was sieved using almrn sieve, and was then blended with appropriate quantities of themagnesium stearate (lubricant) and microcrystalline cellulose, mixingfor 15 minutes. The mixture was then compacted to form tablets havingthe following characteristics:

weight: 950 mg hardness: 12-16 KP time of dispersal: 10-15 seconds (37°C.), in water 20-25 seconds (20° C.)

These tablets could be provided in the above-described uncoated statefor dispersion in water prior to swallowing, or could be film coated forswallowing.

EXAMPLE 7

Encapsulated Formulation

The granulate of example 3 was made up into a loose compact under gentlepressure together with an amount of magnesium stearate lubricant tototal 0.34% by weight of the total compact. This loose compact wassealed into gelatin capsules containing the following mixture:

Component Weight mg. Weight % Amoxycillin trihydrate: 573.91¹ 96.8CLPVP: 17 2.9 magnesium stearate: 2 0.34 ¹corresponds to 500 mgamoxycillin free acid

EXAMPLE 8

Sachet Formulation

Component Weight mg. Weight % Amoxycillin trihydrate Potassium 2711.176.12 clavulanate/syloid AL-1 granulate blend 1:1 Polyplasdone XL driedPolyplasdone XL dried 13.5 0.38 Lemon dry flavour 408.0 11.45 Strawberrydry flavour 132.0 3.71 Peach dry flavour 102.0 2.86 extra granularAspartame 45.0 1.26 Xantham Gum 150.0 4.21

Granules were in a manner identical to that of example 1, i.e. bymilling and sieving of the granulate components, followed by rollercompaction (50 KN) and granulation. The granules could be made up into amixture suitable for a sachet presentation with the extra-granularexcipients.

The granulate of this example could be supplied confining appropriateweights of amoxycillin/clavulanate in a sachet, and is also suitable formaking up into syrup formulations. For example the weights listed may bemade up into 60 ml to produce a 156.25 mg/5 ml syrup or double thelisted weights may be made up into 60 ml to produce a 312.5 mg0.5 mlsyrup. These syrups do not contain any added sugar.

EXAMPLE 9

Granulate

Component Weight mg. Weight % Amoxycillin trihydrate 581.4¹ 64.0Potassium clavulanate 152.4² 16.8 Syloid AL-1 152.4 16.8 as granulatePolyplasdone XL dried 22.0 2.42 ¹corresponds to 500 mg amoxycillin freeacid. ²corresponds to 125 mg free clavulanic acid.

Granules are prepared using this mixture in a manner identical to thatof example 8. These granules are suitable for supply in a sachet,together with flavour and sucrose in the proportions listed below forthe quantity of granules listed above per sachet:

Lemon dry flavour 136.0 mg Strawberry dry flavour 44.0 mg Peach dryflavour 34.0 mg Sucrose to 3500 mg

Sachets containing other weights of amoxycillin, e.g. 250 or 125 mgcould be made up using proportional amounts of the weights listed andmade up to 1750 mg total weight with sucrose.

EXAMPLE 10

Tablet

Component Weight mg. Weight % Amoxycillin trihydrate 581.4¹ 61.2Potassium clavulanate 152.4² 16.0 Syloid AL-1 152.4 16.0 as granulatePolyplasdone XL dried 17.4 1.83 Dry flavour (Peppermint or 6.0 0.63mandarin) Polyplasdone XL dried 25.0 2.63 Aspartame 15.0 1.58 extragranulate Colouring 5.0 0.53 Magnesium stearate 2.5 0.26 ¹corresponds to500 mg amoxycillin free acid. ²corresponds to 125 mg free clavulanicacid.

Granules are prepared using this mixture in a manner identical to thatof example 8. The flavour, polyplasdone XL, colouring and magnesiumstearate were sieved then blended with the granulate. The aspartame wasthen added, and this mixture was then compressed into tablets on aconventional tabletting machine. This tablet contains 625.0 mg of theamoxycillin: clavulanate combination, and the quantities used may behalved to prepare a tablet containing 312.5 mg.

EXAMPLE 11

Tablet

Component Weight mg. Weight % Amoxyciliin trihydrate 290.7¹ 46.3Potassium clavulanate 152.4² 24.3 Syloid AL-1 152.4 24.3 as granulatePolyplasdone XL dried 8.7 1.38 Dry flavour (Peppermint or 3.0 0.48mandarin) Polyplasdone XL dried 12.5 2.00 Aspartame 7.5 1.19 extragranulate Colouring 2.5 0.39 Magnesium stearate 1.25 0.20 ¹correspondsto 250 mg amoxycillin free acid. ²corresponds to 125 mg free clavulanicacid.

Tablets were made from this mixture using a procedure identical to thatof example 10.

EXAMPLE 12

Sachet or Syrup Formulations

Component Weight mg w + % Amoxycillin:potassium clavulanate granulate¹2255.6 63.3 4:1 w:w + 3 wt % CLPVP CLPVP 13.5 0.38 Lemon dry flavour408.0 11.46 Strawberry dry flavour 132.0 3.71 Peach dry flavour 102.02.86 Silicon dioxide USNF 450.0 12.64 (Syloid AL-1) Aspartame 45.0 1.26Xantham gum 150.0 4.21 Total weight 3561.6 100.0 ¹amox: clav expressedas free acid.

The granulate was prepared using the procedure of example 8. Thisformulation could be supplied in a sachet, or could be made up into asyrup, for example at concentrations of 3561.6 mg/60 ml or 7123.2 mg/60ml or 7123.2 mg/60 ml (=156.25 and 312.5 mg amoxycillin: clavulanate/5ml respectively). To adjust the syrup to a suitable viscosity and pH,aerosil 200, succinic acid and/or methocel E-15 (dry) may be used.

EXAMPLE 13

Sachet Formulation

Component Weight (mg) w + % Granulate (Amox:Kclav 500 250 125 875  7-254:1 or 7:1 + 3% PVP) Lemon dry flavour 136 68 34  136) Strawberry dryflavour 44 22 11   44)   3-6.1 Peach dry flavour 34 17 8.5   34) SiliconDioxide U.S.N.F. 150 75 37.5 150 2.1-4.3 (Syloid AL-1) Sucrose to 35001750 1750 3500  to 100 (1) weights and Amox/Kclav expressed as freeacid.

The granulate was prepared using the procedure of example 8, and wasthen mixed with the other excipients.

EXAMPLE 14

Tablet Formulation

Amox: clav¹ 4:1 4:1 2:1 7:1 Component weight (mg) w + % Granulate 2751.9 376.0 452.1 1201.3 70.90 Dry Flavour 3 6.0 3.0 3.0 8.0 0.48-0.63Poliplasdone XL 100.0 50.0 66.5 110.0  8.1-10.7 dried Aspartame 15.0 7.57.5 15.0 1.1-1.6 Colouring 4-5 2-2.5 2-2.5 4-5  0.3-0.55 Mag. Stearate2.5 1.25 1.25 3.4 0.19-0.26 Silicon Dioxide 950 475 628 1350 to 100Syloid AL-1 to (1) Amox: clav expressed as weight: weight ofamoxycillin: clavulanate free acid. (2) Granulate = amox: clav + 3%CLPVP. (3) Peppermint or mandarin.

The granulate was prepared using the procedure of example 9.

The granulate was prepared using the procedure of example 9. The otherexcipients except aspartame were sieved and blended then mixed with thegranulate. The aspartame was then added, and this mixture was thencompressed into tablets in a conventional tabletting machine. Thistablet contained 625 mg of the amoxycillin:clavulante blend. Tablets ofdifferent strengths could be formulated correspondingly, eg containing1000, 375 or 312.5 mg of the amoxycillin:clavulanate combination.

EXAMPLE 15

Tablet Formulation

Component Weight (mg) w + % Granulate (Amox.Kclav) 751.9 376.0 188.01201.3 71-83 4:1 or 7:1 + 3% PVP Magnesium stearate 2.6 1.3 0.65 3.90.25-0.27 Ph. Eur Silicon Dioxide 44.0 22.0 11.0 44.0   3-4.25 USP/NF(Syloid AL-1) Microcrystalline cellulose Avicel pH 112 850.0 425.0 212.51275.0 1.8-5   dried . . . to Organic film coating yes yes yes yes to100 Actual weight 1050.0 — — 1450.0 (1) amox: clav expressed as freeacid.

The tablet was made up in a manner identical to that of example 14.

The weights and relative proportions of the components of examples 1 to15 could be varied about the figures listed, but suitably are within±10% of those listed, desirably within ±5%, especially ±2.5%.

What is claimed is:
 1. A tablet formulation having a structurecomprising compacted granulates; the granulates comprising amoxicillinoptionally together with an intra-granular disintegrant; the granulatesbeing compacted together into a tablet form together with anextra-granular disintegrant and optionally also together with anextra-granular lubricant, provided that if a lubricant is present theamount of lubricant is less than 0.5% by weight of the total tablet. 2.A tablet formulation according to claim 1 wherein the intra-granulardisintegrant is selected from the group consisting of maize starch, ricestarch, cross linked N-vinyl-2-pyrrolidone (“CLPVP”), sodium starchglycollate, croscarmellose sodium, formaldehyde-casein and combinationsthereof.
 3. A tablet formulation according to claim 2 wherein theproportion of intra-granular disintegrant is 0.1 to 10 wt % of theweight of the granulate.
 4. A tablet formulation according to claim 1 inwhich the intra-granular disintegrant is CLPVP or sodium starchglycollate, and optionally one or more diluent(s), in a proportion 70-99wt % medicament, 1-5 wt % disintegrant and up to 30 wt % diluent.
 5. Atablet formulation according to claim 1 wherein the granulate comprises70 wt % or more of the tablet weight.
 6. A tablet formulation accordingto claim 1 in which the extra-granular disintegrant is selected from thegroup consisting of maize starch, rice starch, CLPVP, sodium starchglycollate, croscarmellose sodium, microcrystalline or microfinecellulose, low-substituted hydroxypropylcellulose, cross-linked sodiumcarboxymethylcellulose, swellable ion exchange resins,formaldehyde-casein, and alginates.
 7. A tablet formulation according toclaim 1 wherein the proportion of extra-granular disintegrant in thetablet is between 0.1-25 wt % of the total tablet weight.
 8. A tabletformulation according to claim 1 which contains 0-0.35 wt % lubricant.9. The tablet formulation according to claim 1 wherein the amoxicillinis present in an amount of 375 to 1000 mg per tablet.
 10. The tabletformulation according to claim 9 wherein the amoxicillin is amoxicillintrihydrate.
 11. A method of treating a bacterial infection in a mammalin need thereof, which method comprises administering to said mammal,and effective amount of a formulation according to claim 1.